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Npas4 Regulates Excitatory-Inhibitory Balance within Neural Circuits through Cell-Type-Specific Gene Programs
Open accessAbstract
The nervous system adapts to experience by inducing a transcriptional program that controls important aspects of synaptic plasticity. Although the molecular mechanisms of experience-dependent plasticity are well characterized in excitatory neurons, the mechanisms that regulate this process in inhibitory neurons are only poorly understood. Here, we describe a transcriptional program that is induced by neuronal activity in inhibitory neurons. We find that, while neuronal activity induces expression of early-response transcription factors such as Npas4 in both excitatory and inhibitory neurons, Npas4 activates distinct programs of late-response genes in inhibitory and excitatory neurons. These late-response genes differentially regulate synaptic input to these two types of neurons, promoting inhibition onto excitatory neurons while inducing excitation onto inhibitory neurons. These findings suggest that the functional outcomes of activity-induced transcriptional responses are adapted in a cell-type-specific manner to achieve a circuit-wide homeostatic response.
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“Npas4 regulates excitatory synapse formation through the induction of a transcriptional program in SST+ interneurons that involves the expression of several synaptic scaffolding proteins and the shaker-like potassium channel Kv1.1 (Spiegel et al., 2014).”
From Development and Functional Diversification of Cortical Interneurons (2018) · cites this paper as Spiegel et al., 2014
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Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860
Bolstad, B. M., Irizarry, R. A., Åstrand, M., & Speed, T. P. (2003) · Bioinformatics · doi:10.1093/bioinformatics/19.2.185 · Cited by 8,314
A robust and high-throughput Cre reporting and characterization system for the whole mouse brain
Madisen, L., Zwingman, T. A., Sunkin, S. M., Oh, S. W., Zariwala, H. A., Gu, H., Ng, L. L., Palmiter, R. D., Hawrylycz, M. J., Jones, A. R., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2467 · Cited by 6,907
Histone H3K27ac separates active from poised enhancers and predicts developmental state
Creyghton, M. P., Cheng, A. W., Welstead, G. G., Kooistra, T., Carey, B. W., Steine, E. J., Hanna, J., Lodato, M. A., Frampton, G. M., Sharp, P. A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1016071107 · Cited by 4,302
Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes
Whyte, W. A., Orlando, D. A., Hnisz, D., Abraham, B. J., Lin, C. Y., Kagey, M. H., Rahl, P. B., Lee, T. I., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.03.035 · Cited by 4,143
Interneurons of the neocortical inhibitory system
Markram, H., Toledo-Rodriguez, M., Wang, Y., Gupta, A., Silberberg, G., & Wu, C. (2004) · Nature Reviews Neuroscience · doi:10.1038/nrn1519 · Cited by 2,954 · cited 3×
“Balance within Neural Circuits through”
SINGLE-CELL RESPONSES IN STRIATE CORTEX OF KITTENS DEPRIVED OF VISION IN ONE EYE
Wiesel, T. N., & Hubel, D. H. (1963) · Journal of Neurophysiology · doi:10.1152/jn.1963.26.6.1003 · Cited by 2,628 · cited 2×
“Balance within Neural Circuits through”
Widespread transcription at neuronal activity-regulated enhancers
Kim, T.-K., Hemberg, M., Gray, J. M., Costa, A. M., Bear, D. M., Wu, J., Harmin, D. A., Laptewicz, M., Barbara-Haley, K., Kuersten, S., et al. (2010) · Nature · doi:10.1038/nature09033 · Cited by 2,450 · cited 2×
“ChIP-seq data sets (Kim et al., 2010) generated from mixed cortical cultures containing both excitatory and inhibitory neurons using anti-Npas4, -CBP, -H3K4me1, and -H3K4me3 antibodies revealed that most Npas4-regulated genes are located near candidate regulatory elements (6 out of 9 genes regulated by Npas4 in MGE on…”
Self-citationCritical period plasticity in local cortical circuits
Hensch, T. K. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1787 · Cited by 2,323 · cited 2×
“Balance within Neural Circuits through”
Cortical inhibitory neurons and schizophrenia
Lewis, D. A., Hashimoto, T., & Volk, D. W. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1648 · Cited by 2,297 · cited 2×
“Balance within Neural Circuits through”
A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex
Taniguchi, H., He, M., Wu, P., Kim, S., Paik, R., Sugino, K., Kvitsani, D., Fu, Y., Lu, J., Lin, Y., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.07.026 · Cited by 1,828
How Inhibition Shapes Cortical Activity
Isaacson, J. S., & Scanziani, M. (2011) · Neuron · doi:10.1016/j.neuron.2011.09.027 · Cited by 1,678 · cited 2×
“Balance within Neural Circuits through”
Ca2+ Influx Regulates BDNF Transcription by a CREB Family Transcription Factor-Dependent Mechanism
Tao, X., Finkbeiner, S., Arnold, D. B., Shaywitz, A. J., & Greenberg, M. E. (1998) · Neuron · doi:10.1016/s0896-6273(00)81010-7 · Cited by 1,561
Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons
Rudy, B., Fishell, G., Lee, S., & Hjerling‐Leffler, J. (2011) · Developmental Neurobiology · doi:10.1002/dneu.20853 · Cited by 1,420 · cited 2×
“Balance within Neural Circuits through”
Gorski, J. A., Talley, T., Qiu, M. S., Puelles, L., Rubenstein, J. L. R., & Jones, K. R. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-15-06309.2002 · Cited by 1,403
K+ channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons
Hoffman, D. A., Magee, J. C., Colbert, C. M., & Johnston, D. (1997) · Nature · doi:10.1038/43119 · Cited by 1,392 · cited 8×
“Kcna1 encodes the shaker-like potassium channel Kv1.”
InfluentialA Developmental Switch in the Response of DRG Neurons to ETS Transcription Factor Signaling
Hippenmeyer, S., Pecho‐Vrieseling, E., Sigrist, M., Portmann, T., Laengle, C., Ladle, D. R., & Arber, S. (2005) · PLoS Biology · doi:10.1371/journal.pbio.0030159 · Cited by 1,101
The origin and specification of cortical interneurons
Wonders, C. P., & Anderson, S. A. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn1954 · Cited by 980 · cited 1×
“…neuronal cultures highly enriched for these neurons by taking advantage of the fact that, early in their development, inhibitory neurons are localized to specialized regions of the embryonic brain, the ganglionic eminences, that are devoid of excitatory neurons (Wonders and Anderson, 2006).”
Cell-type-specific isolation of ribosome-associated mRNA from complex tissues
Sanz, E., Yang, L., Su, T., Morris, D. R., McKnight, G. S., & Amieux, P. S. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0907143106 · Cited by 976 · cited 3×
“To determine whether neuronal activity driven by sensory experience in vivo also induces shared early-response genes and distinct sets of late-response genes in inhibitory and excitatory neurons, we generated mice heterozygous for alleles of either Emx1-Cre (expressed specifically in excitatory neurons) or Gad2-Cre (e…”
MethodInfluentialProduction and purification of lentiviral vectors
Tiscórnia, G., Singer, O., & Verma, I. M. (2006) · Nature Protocols · doi:10.1038/nprot.2006.37 · Cited by 974
Defined types of cortical interneurone structure space and spike timing in the hippocampus
Somogyi, P., & Klausberger, T. (2005) · The Journal of Physiology · doi:10.1113/jphysiol.2004.078915 · Cited by 927 · cited 2×
“Balance within Neural Circuits through”
Flavell, S. W., & Greenberg, M. E. (2008) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.31.060407.125631 · Cited by 832 · cited 4×
“Balance within Neural Circuits through”
InfluentialXia, Z., Dudek, H., Miranti, C. K., & Greenberg, M. E. (1996) · Journal of Neuroscience · doi:10.1523/jneurosci.16-17-05425.1996 · Cited by 787
Disynaptic Inhibition between Neocortical Pyramidal Cells Mediated by Martinotti Cells
Silberberg, G., & Markram, H. (2007) · Neuron · doi:10.1016/j.neuron.2007.02.012 · Cited by 768 · cited 4×
“SSTneurons largely receive excitatory input from local cortical afferents, so levels of Npas4 in SST neuronsmay specifically reflect activity levels in local cortical circuits and could potentially function to fine-tune the amount of feedback inhibition broadcasted by SST neurons throughout the local microcircuit (Sil…”
InfluentialToo many cooks? Intrinsic and synaptic homeostatic mechanisms in cortical circuit refinement
Turrigiano, G. (2011) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-060909-153238 · Cited by 671 · cited 2×
“…consistent with previous reports of strengthening of excitatory synapses onto inhibitory neurons in response to elevated levels of circuit activity (Turrigiano, 2011), supporting the hypothesis that increasing excitation to inhibitory neurons may be a general principle governing the nervous…”
Activity-dependent regulation of inhibitory synapse development by Npas4
Lin, Y., Bloodgood, B. L., Hauser, J. L., Lapan, A. D., Koon, A. C., Kim, T.-K., Hu, L. S., Malik, A. N., & Greenberg, M. E. (2008) · Nature · doi:10.1038/nature07319 · Cited by 639 · cited 5×
“This function is different from Npas4’s previously described function in excitatory neurons (Bloodgood et al., 2013; Lin et al., 2008) and suggests that Npas4 functions in a cell-type-specific manner to control excitatory-inhibitory balance.”
InfluentialSelf-citationChattopadhyaya, B., Di Cristo, G., Higashiyama, H., Knott, G. W., Kuhlman, S. J., Welker, E., & Huang, Z. J. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.1851-04.2004 · Cited by 596 · cited 2×
“Balance within Neural Circuits through”
Dense Inhibitory Connectivity in Neocortex
Fino, E., & Yuste, R. (2011) · Neuron · doi:10.1016/j.neuron.2011.02.025 · Cited by 532 · cited 2×
“Because SST neurons receive local excitatory input and form dense networks of inhibitory synapses onto nearby pyramidal neurons (Fino and Yuste, 2011), we hypothesized that they are optimally situatedwithin a cortical circuit to utilize activity-induced transcriptional pathways to read out local levels of activity and…”
Stenman, J. M., Toresson, H., & Campbell, K. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-01-00167.2003 · Cited by 518
Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling
Fazzari, P., Paternain, A. V., Valiente, M., Pla, R., Luján, R., Lloyd, K., Lerma, J., Marín, O., & Rico, B. (2010) · Nature · doi:10.1038/nature08928 · Cited by 501 · cited 2×
“Npas4-Regulated Genes Induced by Sensory Experience in SST Neurons Can Modify Excitatory Synapses Despite the recent identification of molecules that shape the synaptic connectivity of inhibitory neurons (Fazzari et al., 2010; Sylwestrak andGhosh, 2012), themolecular mechanisms underlying the plasticity of synaptic in…”
Large-scale oscillatory calcium waves in the immature cortex
Garaschuk, O., Linn, J., Eilers, J., & Konnerth, A. (2000) · Nature Neuroscience · doi:10.1038/74823 · Cited by 493 · cited 1×
“At P10–P12, calcium waves sweep through the cortex before eye opening, providing a source of neuronal activity to activate Npas4 (Garaschuk et al., 2000), and widespread Npas4 expression is observed in SST neurons at P11 following kainate seizure induction (Figure S2D).”
Synaptic clustering of AMPA receptors by the extracellular immediate-early gene product narp.
O’Brien, R. J., Xu, D., Petralia, R. S., Steward, O., Huganir, R. L., & Worley, P. (1999) · Neuron · doi:10.1016/s0896-6273(00)80782-5 · Cited by 471 · cited 9×
“Kcna1 encodes the shaker-like potassium channel Kv1.”
InfluentialFunding for malaria genome sequencing
Hoffman, S., Bancroft, W., Michael, G., James, S., Burroughs, E. C. B., Stephenson, J., & Morgan, M. (1997) · Nature · doi:10.1038/42571 · Cited by 461 · cited 7×
“Kcna1 encodes the shaker-like potassium channel Kv1.”
InfluentialFlavell, S. W., Kim, T.-K., Gray, J. M., Harmin, D. A., Hemberg, M., Hong, E. J., Markenscoff-Papadimitriou, E., Bear, D. M., & Greenberg, M. E. (2008) · Neuron · doi:10.1016/j.neuron.2008.11.029 · Cited by 440
Detection of spontaneous synaptic events with an optimally scaled template
Clements, J. D., & Bekkers, J. M. (1997) · Biophysical Journal · doi:10.1016/s0006-3495(97)78062-7 · Cited by 401
Bortone, D., & Polleux, F. (2009) · Neuron · doi:10.1016/j.neuron.2009.01.034 · Cited by 387
Hong, E. J., McCord, A. E., & Greenberg, M. E. (2008) · Neuron · doi:10.1016/j.neuron.2008.09.024 · Cited by 366
Narp regulates homeostatic scaling of excitatory synapses on parvalbumin-expressing interneurons
Chang, M. C., Park, J. M., Pelkey, K. A., Grabenstatter, H. L., Xu, D., Linden, D. J., Sutula, T. P., McBain, C. J., & Worley, P. F. (2010) · Nature Neuroscience · doi:10.1038/nn.2621 · Cited by 316
The activity-dependent transcription factor NPAS4 regulates domain-specific inhibition
Bloodgood, B. L., Sharma, N., Browne, H. A., Trepman, A. Z., & Greenberg, M. E. (2013) · Nature · doi:10.1038/nature12743 · Cited by 310
Self-citationOkaty, B. W., Miller, M. N., Sugino, K., Hempel, C. M., & Nelson, S. B. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.0105-09.2009 · Cited by 309
Npas4 Regulates a Transcriptional Program in CA3 Required for Contextual Memory Formation
Ramamoorthi, K., Fropf, R., Belfort, G. M., Fitzmaurice, H. L., McKinney, R. M., Neve, R. L., Otto, T., & Lin, Y. (2011) · Science · doi:10.1126/science.1208049 · Cited by 305 · cited 2×
“Npas4 deletion leads to an impairment of several forms of neuronal plasticity, suggesting that expression of Npas4 is necessary for the nervous system to adapt to sensory input (Maya-Vetencourt et al., 2012; Ploski et al., 2011; Ramamoorthi et al., 2011).”
Kullmann, D. M., Moreau, A. W., Bakiri, Y., & Nicholson, E. (2012) · Neuron · doi:10.1016/j.neuron.2012.07.030 · Cited by 234 · cited 1×
“Excitatory synaptic inputs to inhibitory neurons also undergo changes in response to activity, including short- and long-lasting plasticity (Kullmann et al., 2012).”
Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR
Ebert, D. H., Gabel, H. W., Robinson, N. D., Kastan, N. R., Hu, L. S., Cohen, S., Navarro, A. J., Lyst, M. J., Ekiert, R., Bird, A. P., et al. (2013) · Nature · doi:10.1038/nature12348 · Cited by 227
Self-citationStructural basis for the role of inhibition in facilitating adult brain plasticity
Chen, J. L., Lin, W. C., Cha, J. W., So, P. T., Kubota, Y., & Nedivi, E. (2011) · Nature Neuroscience · doi:10.1038/nn.2799 · Cited by 214
Elfn1 Regulates Target-Specific Release Probability at CA1-Interneuron Synapses
Sylwestrak, E. L., & Ghosh, A. (2012) · Science · doi:10.1126/science.1222482 · Cited by 151
Polleux, F., & Ghosh, A. (2002) · Science Signaling · doi:10.1126/stke.2002.136.pl9 · Cited by 143
Gene Expression in Cortical Interneuron Precursors is Prescient of their Mature Function
Batista‐Brito, R., Machold, R. P., Klein, C., & Fishell, G. (2008) · Cerebral Cortex · doi:10.1093/cercor/bhm258 · Cited by 133
Coutellier, L. D., Beraki, S., Ardestani, P. M., Saw, N. L., & Shamloo, M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046604 · Cited by 112
The Neuronal PAS Domain Protein 4 (Npas4) Is Required for New and Reactivated Fear Memories
Ploski, J. E., Monsey, M. S., Nguyen, T., Dileone, R., & Schafe, G. E. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023760 · Cited by 101
Experience‐dependent expression of NPAS4 regulates plasticity in adult visual cortex
Maya‐Vetencourt, J. F., Tiraboschi, E., Greco, D., Restani, L., Cerri, C., Auvinen, P., Maffei, L., & Ċastrén, E. (2012) · The Journal of Physiology · doi:10.1113/jphysiol.2012.234237 · Cited by 63 · cited 1×
“Npas4 deletion leads to an impairment of several forms of neuronal plasticity, suggesting that expression of Npas4 is necessary for the nervous system to adapt to sensory input (Maya-Vetencourt et al., 2012; Ploski et al., 2011; Ramamoorthi et al., 2011).”
Neuronal Pentraxins Mediate Silent Synapse Conversion in the Developing Visual System
Koch, S. M., & Ullian, E. M. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.4893-09.2010 · Cited by 55 · cited 2×
“Considering Narp’s well-known role in promoting AMPA receptor accumulation and the stabilization of non-spiny excitatory synapses (Koch and Ullian, 2010; O’Brien et al., 1999), these data suggest that Npas4 executes its effect on excitatory synapses in SST neurons at least in part via transcriptional induction of Nptx…”
Lee, H. W., Choi, J., Shin, H., Kim, K., Yang, J., Na, M., Choi, S. Y., Kang, G. B., Eom, S. H., Kim, H., et al. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.3112-08.2008 · Cited by 53
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“Npas4 showed modest up-regulation of expression 30 min and 1 hr after stimulation (2.2 and 2.1 respectively) (Figure 2A and B), well within the induction window reported in vivo for the cortex (Lin et al., 2008; Spiegel et al., 2014).”
InfluentialExcitatory/Inhibitory Balance and Circuit Homeostasis in Autism Spectrum Disorders
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Mo, A., Mukamel, E. A., Davis, F. P., Luo, C., Henry, G. L., Picard, S., Urich, M. A., Nery, J. R., Sejnowski, T. J., Lister, R., et al. (2015) · Neuron · doi:10.1016/j.neuron.2015.05.018 · Cited by 739
“Likewise, hypo-DMRs and differential ATAC-seq peaks in PV and VIP neurons provide a resource for identifying AP-1 and NPAS4 targets that orchestrate distinct activity-dependent responses in inhibitory neurons (Spiegel et al., 2014).”
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Metadata
- Authors
- Spiegel, I., Mardinly, A. R., Gabel, H. W., Bazinet, J. E., Couch, C. H., Tzeng, C. P., Harmin, D. A., & Greenberg, M. E.
- Affiliations
- Harvard University (US)
- Corresponding author
- Greenberg, Michael E.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-05
- Volume
- 157
- Issue
- 5
- Pages
- 1216-1229
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4089405
- OpenAlex
- W2079540311
- Cited by
- 416
- References
- 52
- Citations by year
- 2026: 31 · 2025: 49 · 2024: 41 · 2023: 28 · 2022: 38 · 2021: 37 · 2020: 29 · 2019: 34 · 2018: 31 · 2017: 32 · 2016: 34 · 2015: 23 · 2014: 8
- FWCI
- 14.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01ns048276-15)
- National Institute of Mental Health (T32MH020017)
- National Institute of Neurological Disorders and Stroke (R01NS028829, NS048276, R37NS028829)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD018655)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- Npas4, excitation-inhibition balance, inhibitory neurons, excitatory neurons, activity-dependent transcription, synaptic plasticity, homeostatic regulation, neural circuits
- MeSH terms
- Animals, Embryo, Mammalian, Gene Expression Regulation, Neurons, Synapses, Transcription, Genetic, Mice, Knockout, Cell Culture Techniques, Mice, Basic Helix-Loop-Helix Proteins
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